SLC4 base (HCO3−, CO32−) transporters: classification, function, structure, genetic diseases, and knockout models

Pushkin, Alexander; Kurtz, Ira

doi:10.1152/ajprenal.00252.2005

Cited by 152 publications

(195 citation statements)

References 226 publications

(260 reference statements)

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“…AE1 belongs to a subfamily of electroneutral anion exchangers of the SLC4 family of bicarbonate transporters (for review: (7,38,138,144)). The AE1 isoform of the kidney is an N-terminally truncated version of the red blood cell band3/AE1…”

Section: Ae1mentioning

confidence: 99%

Regulated acid–base transport in the collecting duct

Wagner

Devuyst

Bourgeois

et al. 2009

Pflugers Arch - Eur J Physiol

161

142

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The renal collecting system serves the fine-tuning of renal acid-base secretion. Acid-secretory type-A intercalated cells secrete protons via a luminally expressed V-type H(+)-ATPase and generate new bicarbonate released by basolateral chloride/bicarbonate exchangers including the AE1 anion exchanger. Efficient proton secretion depends both on the presence of titratable acids (mainly phosphate) and the concomitant secretion of ammonia being titrated to ammonium. Collecting duct ammonium excretion requires the Rhesus protein RhCG as indicated by recent KO studies. Urinary acid secretion by type-A intercalated cells is strongly regulated by various factors among them acid-base status, angiotensin II and aldosterone, and the Calcium-sensing receptor. Moreover, urinary acidification by H(+)-ATPases is modulated indirectly by the activity of the epithelial sodium channel ENaC. Bicarbonate secretion is achieved by non-type-A intercalated cells characterized by the luminal expression of the chloride/bicarbonate exchanger pendrin. Pendrin activity is driven by H(+)-ATPases and may serve both bicarbonate excretion and chloride reabsorption. The activity and expression of pendrin is regulated by different factors including acid-base status, chloride delivery, and angiotensin II and may play a role in NaCl retention and blood pressure regulation. Finally, the relative abundance of type-A and non-type-A intercalated cells may be tightly regulated. Dysregulation of intercalated cell function or abundance causes various syndromes of distal renal tubular acidosis underlining the importance of these processes for acid-base homeostasis.

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Section: Ae1mentioning

confidence: 99%

Regulated acid–base transport in the collecting duct

Wagner

Devuyst

Bourgeois

et al. 2009

Pflugers Arch - Eur J Physiol

161

142

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“…Prominent examples of such epithelia are the stria vascularis of the inner ear that generates the electrochemical driving force essential for hearing and the corneal endothelial cell layer that is essential for regulation of the fluid composition of the cornea. The ion transporter SLC4A11 was first described in 2001 (1) as a distant member of the Slc4 family of ion transporters that mediate the transport of bicarbonate, chloride, and sodium (2,3). Based on its structural similarity to the plant borate transporter (4), a function as a mammalian borate transporter was discussed (5).…”

mentioning

confidence: 99%

SLC4A11 Prevents Osmotic Imbalance Leading to Corneal Endothelial Dystrophy, Deafness, and Polyuria

Gröger

Fröhlich

Maier

et al. 2010

Journal of Biological Chemistry

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Maintenance of ion concentration gradients is essential for the function of many organs, including the kidney, the cornea, and the inner ear. Ion concentrations and fluid content in the cornea are regulated by endothelial cells that separate the collagenous avascular corneal stroma from the anterior eye chamber. Failure to maintain correct ion concentrations leads to swelling and destruction of the cornea. In the inner ear, the stria vascularis is responsible for generating proper ion concentrations in the endolymph, which is essential for hearing. Mutations of SLC4A11 in humans lead to syndromes associated with corneal dystrophy and perceptive deafness. The molecular mechanisms underlying these symptoms are poorly understood, impeding therapeutic interventions. The ion transporter SLC4A11 mediates sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions in vitro. Here, we show that SLC4A11 is expressed in the endothelial cells of the cornea where it prevents severe morphological changes of the cornea caused by increased sodium chloride concentrations in the stroma. In the inner ear, SLC4A11 is located in fibrocytes underlying the stria vascularis. Loss of SLC4A11 leads to morphological changes in the fibrocytes and deafness. We demonstrate that SLC4A11 is essential for the generation of the endocochlear potential but not for regulation of potassium concentrations in the endolymph. In the kidney, SLC4A11 is expressed in the thin descending limb of Henle loop. SLC4A11 is essential for urinary concentration, suggesting that SLC4A11 participates in the countercurrent multiplication that concentrates urine in the kidney medulla.

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“…HCO 3 exchangers (1). A single member of the family encoded by the SLC4A11 gene does not transport bicarbonate (carbonate) (2,3).…”

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confidence: 99%

Slc4a11 Gene Disruption in Mice

López

Rosenblatt

Kim

et al. 2009

Journal of Biological Chemistry

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NaBC1 (the SLC4A11 gene) belongs to the SLC4 family of sodium-coupled bicarbonate (carbonate) transporter proteins and functions as an electrogenic sodium borate cotransporter. Mutations in SLC4A11 cause either corneal abnormalities (corneal hereditary dystrophy type 2) or a combined auditory and visual impairment (Harboyan syndrome). The role of NaBC1 in sensory systems is poorly understood, given the difficulty of studying patients with NaBC1 mutations. We report our findings in Slc4a11 ؊/؊ mice generated to investigate the role of NaBC1 in sensorineural systems. In wild-type mice, specific NaBC1 immunoreactivity was detected in fibrocytes of the spiral ligament, from the basal to the apical portion of the cochlea. NaBC1 immunoreactivity was present in the vestibular labyrinth, in stromal cells underneath the non-immunoreactive sensory epithelia of the macula utricle, sacule, and crista ampullaris, and the membranous vestibular labyrinth was collapsed. Both auditory brain response and vestibular evoked potential waveforms were significantly abnormal in Slc4a11 ؊/؊ mice. In the cornea, NaBC1 was highly expressed in the endothelial cell layer with less staining in epithelial cells. However, unlike humans, the corneal phenotype was mild with a normal slit lamp evaluation. Corneal endothelial cells were morphologically normal; however, both the absolute height of the corneal basal epithelial cells and the relative basal epithelial cell/total corneal thickness were significantly increased in Slc4a11 ؊/؊ mice. Our results demonstrate for the first time the importance of NaBC1 in the audio-vestibular system and provide support for the hypothesis that SLC4A11 should be considered a potential candidate gene in patients with isolated sensorineural vestibular hearing abnormalities.The SLC4 transporter family consists of proteins that mediate bicarbonate (carbonate) transport and include Cl-HCO 3 exchangers, Na/HCO 3 cotransporters, and sodium-driven Cl-HCO 3 exchangers (1). A single member of the family encoded by the SLC4A11 gene does not transport bicarbonate (carbonate) (2, 3). On the basis of sequence homology with other members of the SLC4 family, the protein encoded by SLC4A11 was initially called BTR1 (bicarbonate transporter 1) (2). Subsequently, motivated by its homology with the borate transporter BOR1 in Arabidopsis (4), experiments by Park et al. (3) reported that the transporter functioned in the presence of borate as an electrogenic sodium-borate cotransporter and was renamed NaBC1.Mutations in the SLC4A11 gene are responsible for corneal hereditary dystrophy type 2 (CHED2) 4 and Harboyan syndrome (5-14). In addition to corneal dystrophy, patients with Harboyan syndrome have perceptive hearing loss and nystagmus (7,14). Whether all patients with CHED2 have undiagnosed hearing abnormalities is currently unknown. Heterozygous single nucleotide polymorphisms for SLC4A11 have also been identified in Chinese and Indian patients with Fuchs dystrophy, the most common dystrophic cause of endothelial failure in the...

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SLC4 base (HCO₃⁻, CO₃^2⁻) transporters: classification, function, structure, genetic diseases, and knockout models

Cited by 152 publications

References 226 publications

Regulated acid–base transport in the collecting duct

Regulated acid–base transport in the collecting duct

SLC4A11 Prevents Osmotic Imbalance Leading to Corneal Endothelial Dystrophy, Deafness, and Polyuria

Slc4a11 Gene Disruption in Mice

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